Therapeutically active 10-methoxy-deserpidine

ABSTRACT

DISCLOSED ARE LEVOROTATORY 10-METHOXY-DESERPIDINE AND RELATED COMPOUNDS USEFULS AS HYPOTENSIVE AGENTS.

United States Patent 3,647,801 THERAPEUTICALLY ACTIVE -METHOXY- DESERPIDINE Theodor Petrzilka, Zurich, and Albert Hofmann, Hansruedi Schenk, and Franz Troxler, Basel, Switzerland, and Albert Frey and Hans Ott, Hanover, N.J., assignors to Sandoz Ltd. (also known as Sandoz A.G.), Basel, Switzerland No Drawing. Continuation-impart of application Ser. No. 728,112, Apr. 14, 1958. This application Dec. 12, 1963, Ser. No. 329,972

Int. Cl. C07d 57/10 US. Cl. 260-287 A 1 Claim ABSTRACT OF THE DISCLOSURE Disclosed are levorotatory IO-methoxy-deserpidine and related compounds useful as hypotensive agents.

The present application is a continuation-in-part of copending application, Ser. No. 728,112, filed Apr. 14, 1958 which matured to US. 3,365,456.

The present invention is primarily concerned with therapeutically active lO-methoxy-deserpidine, i.e. ()-10- methoxy-deserpidine.

Reserpine represents the main alkaloid of the Rauwolfia species, apart from ajmaline which has been known for some time, while deserpidine and rescinnamine represent two of the numerous subsidiary alkaloids which occur in this species of the apocynacees.

In recent years, reserpine, deserpidine, and rescinnamine have attained considerable therapeutic importance, since they permit successful treatment of hypertony and mental disturbances on account of their blood pressure depressant and sedative properties. Admittedly, these alkaloids sometimes give rise to side-eflects which can be unpleasant and in some cases may lead to interruption of treatment. Most frequently, mental depression, tiredness, hyperacidity of the stomach, diarrhoea, dyspnea or asthma, oedema (anti-diuretic effect), and sometimes peptic ulcers, parkinsonism, and attacks of Grand-Mal [H. A. Schroeder and H. M. Perry, J. Amer. Med. Assoc. 159, '839 1955); Editorial, Brit. Med. J. 1955 II, 1378] occur. It is therefore desirable to have available compounds with similar activity, which retain the therapeutically valuable properties 'but which do not exhibit the side-effects of the natural alkaloids or only exhibit them to a reduced degree.

The action of reserpine in laboratory animals, which is determinative of the therapeutic value of the preparation, can be characterized as the resultant of the following action-components:

(a) potentiation of the action of narcotics (:expression of sedatiave effect); (b) reduction in blood pressure.

Another characteristic property of reserpine is its convulsion facilitating effect (c), a property which is responsible for some of the above-mentioned serious side-effects. Both deserpidine and rescinnamine also have these three properties; furthermore, in the case of the natural alkaloids, the individual properties are always present in the same relationship to each other.

In sharp contrast thereto, the present invention, by careful selective substitution of the reserpine molecule, enables the various properties to be individually strengthened or suppressed as desired. Thus, comparative tests between the therapeutically active l0-rnethoxy-deserpidine and reserpine show that the convulsion promoting as well as the narcosis potentiating action of reserpine have entirely disappeared in the case of IO-mthoxy-deserpidine while the Patented Mar. 7, 1972 Narcosis potentiation Lowfering 0 con- Blood EDso Subcutavulsive pressure mg. kg., neous, threshold drop in Compound 3 hrs. 30 hrs. in percent percent Reserpine 0. 11 0. 47 56 37 l0-methoxydeserpidine 1. 5 5. 0 0 43 ll-methyldeserpidine 0. 13 1. 0 47 29 Accordingly, the active IO-methoxy-deserpidine of this invention possesses practically only the hypotensive properties of reserpine but not its central depressant and convulsant activities and therefore represents a compound qualitatively different from the natural alkaloids. The advantage of the above said properties of IO-methoxy-deserpidine in the clinical and especially ambulatory therapy of hypertension is clear since in this situation the convulsion promoting and central depressant actions of the natural alkaloids are undesired and frequently render antihypertensive therapy, with e.g. reserpine, impossible.

The toxicity of the compound is much lower than that of reserpine.

The levorotatory IO-methoxy-deserpidine may be employed for the treatment of all types of arterial hypertension. Treatment may be started with a daily dosage of 20- 30 mg. active principle; this dosage may, if necessary, be increased by 10 mg. weekly, up to mg. daily. Once the desired fall in blood pressure has been achieved, the minimum maintenance dosage may be ascertained by progressively reducing the daily dosage by 10 mg. weekly. The active principle of the present invention can be administered enterally in a conventional manner, for example, it may be compounded with known excipients and given in the form of tablets or suppositories. For example, a suitable pharmaceutical preparation would be one consisting of 10 mg. levorotatory IO-methoxy-deserpidine, 134 mg. lactose, 40 mg. maize starch, 14 mg. talc, and 2 mg. gelatin, per tablet.

The symbol preceding the chemical name in the examples refers to the levorotatory acetoxy acid III, or to the intermediate and end products synthesized from it. Thus, ()-1 l-methyl-de'serpidine and ()-IO-methoxydeserpidine are those optical isomers which correspond to the naturally occurring, physiologically active Rauwolfia alkaloids; like the latter they are levorotatory in pyridine solution.

The following description sets forth a presently preferred method of synthesizing the therapeutically active IO-methoxy-deserpidine of this invention (all temperatures being in degrees centigrade):

EXAMPLE 1 )-1 l-methyl-deserpidine (I) 1,2,3,4,7,8,9,IO-O'CTAHYDRO-2-METHOXY-3-ACE'IOXY- 7-OXO-1-NAPHTHOIC ACID 200 grams of decahydro-2-methoxy-3,5-oxido-6-bromo- 7-oxo-8-hydroxy-l-naphthoic acid lactone II of melting point -167" (corrected) [preparation, of. J. Am. Chem. Soc. 78, 2023 (l956)] are suspended in 5000 milliliters of acetic acid anhydride and treated with 200 grams of zinc dust with intense stirring at a temperature of 40, the reaction vessel being cooled externally with ice-water immediately after addition of the zinc dust. Despite this cooling, the temperature of the solution rises within 2 /2 minutes from 20 to 59, and then rapidly falls again. After a total reaction time of 5 minutes, the zinc dust is filtered oil, the filtrate is evaporated in a water-jet vacuum at 70-80, the residue is dissolved in 250 milliliters of acetone and 400 milliliters of water, the solution is allowed to stand at room temperature for several hours to saponify the mixed anhydrides thus produced and then diluted with 2000 milliliters of water and extracted thrice with chloroform. The solution is dried over sodium sulphate and on evaporation leaves a partially crystalline residue, which yields from acetone-ether 128 grams of l,2,3,4,7,8,9,10- octahydro-Z-methoxy 3 acetoxy-7-oxo 1 naphthoic acid III of melting point 210-215 (uncorrected) corresponding to a yield of about 72% of the theoretical.

(II) -HYDROXY ACID LACTAM (a) Separation into the optical antipodes: 62 grams of racernic acetoxy acid III and 73 grams of strychnine are dissolved in 2 liters of methanol, the clear solution is evaporated to half-volume, whereupon on cooling 50 grams of strychnine salt of the (-)-acetoxy-acid crystallizes out as prisms of melting point 240-241 (uncorrected), [a] =-122 (c.-=0.2, in ethanol). Concentration of the mother liquor yields another 11.5 grams of salt of the same purity, so that the yield amounts to 61.5 grams, i.e. 91% of the theoretical. The strychnine salt of the acetoxy-acid remains in the mother liquor.

To obtain the free ()-acetoxy acid, the produced 61.5 grams of strychnine salt are suspended in 200 milliliters of water and treated, with ice-cooling, with 80 milliliters of 2 N ammonium hydroxide solution. After stirring at for 5 minutes, the sepanated strychnine is filtered oil, the filtrate is treated with hydrochloric acid until acid to Congo, and extracted repeatedy with ethyl acetate. The ethyl acetate extract is dried over sodium sulphate, evaporated to dryness, and the residue recrystallized from methanol, whereupon the ()-acetoxy acid III is obtained as intensely light-retracting plates of melting point 223-225 (uncorrected), [a] =-2l9 (c.'=0.2, in ethanol). Yield 26.6 grams or 86% of the theoretical.

(b) Oxidation of the ()-acetoxy acid, condensation with 6-methyl-trpytamine, reduction, ring closure, and saponification to ()-hydroxy acid lactam: 2.82 grams of 1,2,3,4,7,8,9,l0-octahydro-2-methoxy-3-acetoxy- 7-0x0-1-naphthoic acid H'I are dissolved in 30 milliliters of dioxane, the solution is treated with 30 milligrams of solid osmium tetroxide and then with 11.4 grams of HIO .2H O in 50 milliliters of Water and 50 milliliters of 1 N caustic soda. After allowing to stand at room temperature for hours, the solution is extracted thrice with ethyl acetate, the extract dried over sodium sulphate, filtered, and the filtrate is treated with ethereal diazomethane solution until a permanent yellow color is attained. The solution is evaporated to dryness in vacuo at a bath temperature of about 35, the residue is taken up in milliliters of benzene and treated with a solution of 1.90 grams of 6-methyltryptamine IV in milliliters of benzene. After allowing to stand at room temperature for 10 minutes, 30 milliliters of absolute methanol and 1.8 grams of sodium boron hydride are added, the mixture is warmed on the water bath for 10 minutes, and 30 drops of glacial acetic acid are added to the clear solution. After concentration in vacuo, it is distributed between 1 N hydrochloric acid and methylene chloride. The solution in methylene chloride is washed with water and a saturated solution of common salt, and the aqueous extracts are extracted twice with methylene chloride. The united methylene chloride extracts are dried over sodium sulphate and the solvent is removed in vacuo. The amorphous residue is dissolved in a mixture of 30 milliliters of methanol and 30 milliliters of 1 N sodium hydroxide solution, the solution is heated to boiling under reflux for 90 minutes, acidified with hydrochloric acid until acid to Congo and the major portion of the methanol is removed in vacuo, whereupon 2.3 grams of )-hydroxy acid lactam of the Formula V are obtained, corresponding to a yield of 58% of the theoretical. Poly- 4 hedral from diluted methanol of melting point 153-155 (uncorrected), [a] =I-50 (c.-=0.2, in pyridine).

(III) ()-1l-METHYL-ISODESERPIDIC ACID LACTONE (a) Lactone-lactam: 2.2 grams of ()-hydroxy acid lactam and 1.0 gram of anhydrous sodium acetate are heated to boiling under reflux in a solution of milliliters of benzene and 8 milliliters of acetic anhydride for 15 hours, the substance dissolving within 1 hour. After cooling, the whole is evaporated to dryness in vacuo, and the residue is distributed between sodium hydrogen carbonate solution and methylene chloride. From the amorphous residue (2.0 grams) of the methylene chloride solution the lactone-lactam VI crystallizes from ethyl acetate as rhombohedric plates of melting point 169-171" (corrected), [a] =38 (c.=0.2, in pyridine).

(b) (-)-3-dehydro-l-l-methyl-deserpidic acid lactone: 1.64 grams of the lactone-lactam described under (1113.) is heated under reflux in a solution of 35 milliliters of freshly distilled phosphorus oxychloride in an atmosphere of nitrogen for 2 hours. The brownish solution is evaporated to dryness in vacuo, the residue is dissolved in methylene chloride, the solution is extracted with dilute ammonium hydroxide solution, dried over sodium sulphate, and on concentration and replacement of the methylene chloride by methanol, (-)-11-methyl-3-dehydrodeserpidic acid in lactone VII crystallizes as needles of melting point 301-303 (corrected). ot] (c.=0.2, in pyridine): Yield 80% of the theoretical.

(c) ()-1l-methyl-isodeserpidic acid lactone. 1.15 grams of ()-11-methyl-3-dehydro-deserpidic acid lactone are suspended in a mixture of 15 milliliters of methanol and 15 milliliters of methylene chloride, and the mixture is treated at room temperature in twoportions with 1.3 grams of sodium boron hydride. After the reaction is completed, a little acetic acid is added and the solution is then evaporated to dryness. The remaining residue is distributed between dilute ammonium hydroxide solution and methylene chloride. After evaporation of the solvent, there is obtained ()-1l-methyl-isodeserpidic acid lactone of the Formula VIII as an amorphous residue.

(IV) ()-11-METHYLDESERPIDINE (a) Rearrangement: 1.3 grams of crude ll-methyl-isodeserpidic acid lactone are heated under reflux with 10 milliliters of a solution of xylene/pivalic acid (8:2) for 15 hours in an atmosphere of nitrogen. The solution is then evaporated to dryness in vacuo, and the residue is distributed between methylene chloride and diluted ammonium hydroxide solution. The residue from the methylene chloride solution with alcohol yields crystalline ()-l l-methyl-deserpidic acid lactone IX as needles of melting point 320-330 (corrected), [a] =+24 (c.=0.2 in pyridine). Yield 75% of the theoretical.

(b) ()-11-methyl-deserpidine: 0.38 gram of the ll-methyl-deserpidic acid lactone described under (IVa) is heated under reflux for 1% hours in a dilute sodium methylate solution (prepared by dissolving 60 milligrams of sodium in 20 milliliters of absolute methanol), with exclusion of Water. After cooling, the clear solution is exactly neutralized with dilute hydrochloric acid and evaporated to dryness in vacuo. The residue is then distributed between methylene chloride and dilute ammonium hydroxide solution. The residue from the methylene chloride solution is dissolved in 5 milliliters of pyridine and the solution is treated with 0.45 gram of 3,4,5-trimethoxy-benzoyl chloride and is left to stand at room temperature for 2 hours. The solution is then treated with 1 milliliter of water, allowed to stand at room temperature for hours, rinsed in a separating funnel with methylene chloride, extracted successively with dilute hydrochloric acid, dilute ammonium hydroxide solution, and water, dried over sodium sulphate, and the solvent is evaporated in vacuo. From the residue ()-1 l-methyldeserpidine I (ll-methyl):

OCH:

ocna crystallizes from ethanol as prisms of melting point 269- 27l (corrected), [a] 153 (c. =0.2, in pyridine). Yield 59% of theoretical.

EXAMPLE 2 (I) -10-METHOXY-DESERPIDINE First, l,2,3,4,7,8,9,10-octahydro-2-methoxy-3-acetoxy-7- oxo-l-naphthoic acid III is prepared and separated into the optical antipodes, as described in Example 1 under (I) and (Ila).

(II) HYDROXY-ACID LACTAM (III) -10-METHOXY-ISODESERPIDIC ACID LACTONE (a) Lactone-lactam: 2.5 grams of (-)-hydroxy-acid lactam are heated to boiling under reflux overnight in benzene with acetic anhydride/sodium acetate, as described in Example 1 under (Illa). The lactone lactam VI is obtained from ethyl acetate as needles of melting point l78l80 (uncorrected), [a] =25 (c.=0.4, in pyridine). Yield 77% of the theoretical.

(b) (-)-3-dehydro-l0-methoxyrdeserpidic acid lactone: 0.2 gram of the lactone-lactam described under (a) are treated with phosphorus oxychloride and worked up as described in Example 1 under (IlIb). The compound is obtained from methanol.

Needles of melting point 268-270 (uncorrected), [a] ='+12l (c.=0.3, in pyridine). Yield 92% of the theoretical.

(c) ()-l-methoXy-isodeserpidic acid lactone: 0.17 gram of ()-3-dehydro-l'0-methoxy-deserpidic acid lactone are dissolved in 4 milliliters of 50% aqueous acetic acid and shaken with 0.03 gram of prehydrogenated platinum catalyst in an atmosphere of hydrogen, whereby the amount of hydrogen calculated for 1 mol is almost absorbed in 4 hours. After the hydrogen absorption is completed, the catalyst is filtered off, the filtrate is concentrated in vacuo, the residue is dissolved in methylene chloride, the solution is extracted with dilute ammonium hydroxide solution, dried over sodium sulphate, and evaporated to dryness in vacuo. The residue yields from benzene (-)-l0-methoxyisodeserpidic acid lactone of Formula VIII, needles of melting point 140-142 and 212 (double melting point uncorrected), [u] =9l (c.=0.3, in pyridine). Yield 94% of theory.

(IV) --METHOXY-DESERPIDINE -(a) Rearrangement: 0.765 gram of IO-methoxy-isodeserpidic acid lactone is treated with pivalic acid/Xylene and Worked up as described in Example 1 under (Iva). Chromatographic separation yields 10-methoxy-deserpidic 6 acid lactone IV which is obtained from methanol as needles of melting point 283-284 (corrected),

[]D (c.=0.2, in pyridine).

(b) IO-methoxy-deserpidine: 0.475 gram of 10-methoxydeserpidic acid lactone is converted into the methyl ester according to the method described in Example 1 under (IVb) and this isconverted directly into the 3,4,5- trimethoxy-benzoate (Formula I, 10 methoxy):

(-) -l0-methoxy-deserplrline The compound crystallizes from methanol as needles of melting point -161" (corrected), [a] 161 (c.= 0.3, in pyridine).

The following table shows the formulae of the hereinbefore-na'med compounds:

n cooc our;

@ stands for I q or a vrrl What is claimed is: 1. Levorotatory 10-methoxy-deserpidine.

(References on following page) References Cited UNITED STATES PATENTS 7/1963 Shavel et a1. 167-67 3/1957 Huebner 260 287 5 6/ 1957 Weisenborn 2-60286 10/1958 Kuehne 260286 8 JAMES A. PATTEN, Primary Examiner US. Cl. X.R.

260--236 Y, 287 R, 488 B; 424262 

